At present, humanized antibody preparations are used for targeted chemotherapy of tumors in the Russian Federation (Gain A. M., Bazin I. S. Targeted Therapy of Solid Tumors. A Handbook for Clinician Oncologists. Moscow, 2009).
However, other systems of targeted delivery of various chemotherapeutic agents, which, as a rule, are highly toxic, to tumor cells are intensely devised (US Patent Application 20090047318, 20130287853). Chemotherapeutic agents are incapsulated, for example, into virus-like particles (U.S. Pat. No. 8,324,149, US Patent Application 20080274905) or into virions of RNA-containing bacteriophages (U.S. Pat. Nos. 5,677,124, 6,159,728, US Patent Application 20100167981; Carlee E. Ashley et al. Cell-Specific Delivery of Diverse Cargos by Bacteriophage MS2 Virus-Like Particles//ACS Nano. 2011 Jul. 26; 5(7): 5729-5745 and Jeff E. Glasgowa et al. Osmolyte-Mediated Encapsulation of Proteins inside MS2 Viral Capsids//ACS Nano. 2012 Oct. 23; 6(10): 8658-8664; the abbreviation ACS means the American Chemical Society). By virtue of such an approach, the idea of guaranteed destruction of the MST cells with simultaneously decreasing the exposure of all the organism to the toxic preparations is implemented.
Attention to RNA-containing bacteriophages, to MS2 in particular, as to a means of the targeted delivery, is explained by the simplicity of the virion organization and by absence of receptors specific to it on the surface of human and mammal cells, which excludes its penetration into a cell of these organisms. Researchers try overcoming this “freak” of nature through two successive modifications. Firstly, they try devising conditions for incapsulation of chemotherapeutic agents (Pavel Plevka et al. Structure and Stability of Icosahedral Particles of a Covalent Coat Protein Dimer of Bacteriophage MS2//Protein Science 2009, v. 18 (5), pp. 1653-1661 and Jeff E. Glasgowa et al. Osmolyte-Mediated Encapsulation of Proteins inside MS2 Viral Capsids//ACS Nano. 2012 Oct. 23; 6(10): 8658-8664). Secondly, the virion surface is modified, thus endowing the MS2 bacteriophage particles with the ability to be sorbed on the surface (due to the ligand-receptor interactions) and then penetrate into the cytoplasm of a malignant cell (U.S. Pat. No. 5,534,257; US Patent Application 20130017210; Stacy L. Capehart et al. Controlled Integration of Gold Nanoparticles and Organic Fluorophores Using Synthetically Modified MS2 Viral Capsids//J Am. Chem. Soc. 2013, Feb. 27; 135(8): 3011-3016). However, the above-described researchers' efforts to create targeted delivery systems based on modified viruses are impaired because of the MST cells' genetically determined ability to remove molecules of various toxic chemotherapeutic agents from the cells (Stavrovskaya A. A., T. P. Stromskaya. Transport Proteins of the ABC Family and Multidrug Resistance of Tumor Cells//Biochemistry (Moscow), 2008, v. 73(5), pp. 592-604). The capability to remove chemotherapeutic agents from the cells is implemented by drug resistance proteins or MDR (Multidrug Resistance) proteins (Stephan Wilkens. Structure and Mechanism of ABC Transporters//F1000Prime Reports 2015, 7:14-23).
Along with this, attention should be paid to the fact that penetrating into the cytoplasm of an MST cell via channels specific to potassium ions, radioactive univalent isotope 201Tl is not subject to removal from the cytoplasm (Jean C. Maublant et al. In Vitro Uptake of Technetium-99m-Teboroxime in Carcinoma Cell Lines and Normal Cells: Comparison with Technetium-99m-Sestamibi and Thallium-201//The Journal of Nuclear Medicine November 1993, v. 34(11), pp. 1949-1952; Brismar T. et al. Increased Cation Transport in Mdr1-Gene-Expressing K562 Cells//Cancer Chemother Pharmacol. 1995; v. 36(1): pp. 87-90; M. Fukumoto et al. Scintigraphic Prediction of Resistance to Radiation and Chemotherapy in Patients with Lung Carcinoma//Cancer 1999, Oct. 15, v. 86(8), pp. 1470-1479).
Direct experiments (Spenser P S. et al., Effects of Thallium Salts on Neuronal Mitochondria in Organotypic Cord-Ganglia-Muscle Combination Cultures//The Journal of Cell Biology, 1973, v. 58(1), pp. 79-95) show that the level of toxicity of salts of univalent thallium per culture cell lies within 1 pg (for a normal line of HEK293 cells) and 40 pg (for U251 glioblastoma cells). According to X-ray structural analysis data (Ailong Ke et al. Structural Roles of Monovalent Cations in the HDV Ribozyme//Structure March 2007, v. 15(1), 281-287), interacting with genomic RNA inside an MS2 phage particle (an internal radius of 10 nm), ions of univalent thallium will achieve a concentration lethal for the cell after having absorbed 20 loaded virions. These calculations have served as a basis for creating a system for targeted delivery of thallium salts to MST cells, univalent cations of which are resistant to exposure to the MDR proteins. This invention proposes a solution for therapeutic and diagnostic needs during targeted chemotherapy of MSTs.